Veliparib and Carboplatin in Treating Women With HER2-Negative Metastatic Breast Cancer
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Purpose
This phase I clinical trial is studying the side effects and best dose of veliparib when given with carboplatin and to see how well they work in treating women with HER2-negative metastatic breast cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Veliparib may help carboplatin work better by making tumor cells more sensitive to the drug.
| Condition | Intervention | Phase |
|---|---|---|
|
BRCA1 Mutation Carrier BRCA2 Mutation Carrier Estrogen Receptor-negative Breast Cancer Estrogen Receptor-positive Breast Cancer HER2-negative Breast Cancer Male Breast Cancer Progesterone Receptor-negative Breast Cancer Progesterone Receptor-positive Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Triple-negative Breast Cancer |
Drug: veliparib Other: fluorine F 18 fluorothymidine Other: diagnostic laboratory biomarker analysis Other: pharmacological study Drug: carboplatin |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase 1 Dose-Escalation Study of ABT-888 (Veliparib) in Combination With Carboplatin in HER2 Negative Metastatic Breast Cancer |
- Number and severity of toxicity incidents to measure the safety and tolerability of this treatment combination for the treatment of Her2 negative metastatic breast cancer [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: Yes ]Non-hematologic toxicities will be evaluated via the ordinal CTCAE version 4.0 standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTCAE standard toxicity grading. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
- Clinical response (complete and partial response as well as stable and progressive disease) [ Time Frame: Up to 12 weeks post-treatment ] [ Designated as safety issue: No ]Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).
| Estimated Enrollment: | 42 |
| Study Start Date: | November 2010 |
| Estimated Primary Completion Date: | September 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (veliparib, F 18 fluorothymidine, carboplatin)
Patients receive carboplatin IV over 1 hour on day 1 and veliparib PO twice daily on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo fluorothymidine PET scan and peripheral blood cell and tumor tissue collection periodically for correlative studies.
|
Drug: veliparib
Given PO
Other Name: ABT-888
Other: fluorine F 18 fluorothymidine
Undergo fluorothymidine PET scan
Other Names:
Other: diagnostic laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Drug: carboplatin
Given IV
Other Names:
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose of veliparib along with carboplatin on a 14-day and 21- day schedule in patients with Her2 negative metastatic breast cancer that are estrogen receptor (ER)/progesterone receptor(PR) negative or ER and/or PR positive with defects in Fanconi Anemia (FA) pathway repair genes.
II. To determine the safety and tolerability of combining veliparib on a 14-day and 21-day schedule with carboplatin in this patient population.
III. To determine the preliminary efficacy of this combination in this patient population.
SECONDARY OBJECTIVES:
I. To determine the pharmacodynamic endpoints of PARP inhibition in the tumor by using, A) 3'-[F-18]Fluoro-3'-deoxythymidine Positron Emission Tomography (FLT-PET) of the target lesions, B) circulating tumor cells to detect the induction of the histone variant gammaH2AX, and C) peripheral blood mononuclear cells to assess poly ADP-Ribose (PAR) levels.
II. To determine biomarkers in the primary tumor that may predict antitumor responses to PARP inhibition such as BRCA1/2 protein, FANCD2 nuclear foci formation and expression of miR 155.
OUTLINE: This is a multicenter, dose-escalation study of veliparib.
Patients receive carboplatin intravenously (IV) over 1 hour on day 1 and veliparib orally (PO) twice daily on days 1-7 or 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo fluorothymidine PET scan and peripheral blood cell and tumor tissue collection periodically for correlative studies.
After completion of study treatment, patients are followed up for 12 weeks.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Patients must have histologically or cytologically proven metastatic or locally advanced inoperable breast cancer that fulfills one of the following two criteria:
- Triple-negative breast cancer
- ER and/or PR positive, HER2 negative if their tumors have been shown to be deficient for the FA pathway, based on FATSI immunofluorescence screening
HER negative with a known germline BRCA1/2 mutation
- Patients with ER- and/or PR-positive breast cancer will be consented to have their existing, or to be obtained, paraffin-embedded tumor tissue screened for FA deficiency
Patients with treated brain metastases and life expectancy of greater than 3 months allowed
- Patients with uncontrolled CNS metastasis are not eligible
- Recovered from adverse events due to agents administered more than 4 weeks earlier
- Menopausal status not specified
- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Total bilirubin within normal institutional limits
- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
- Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min
- Patients with known Gilbert syndrome with abnormal unconjugated bilirubin will be eligible
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- Able to swallow pills
No uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situations that would limit compliance with study requirements
Known HIV-infected patients on protease inhibitors are ineligible
- HIV-infected patients with adequate CD4 counts (> 500) and not on protease inhibitors are eligible
Patients with a recent history of seizure (6 months to 1 year) are not eligible
- Patients with a long-term history of seizures and stable on anti-seizure medications may be eligible
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
- Patients may not be receiving any other investigational agents
- No more than 3 prior chemotherapy regimens for metastatic disease
- No prior therapy with veliparib for metastatic disease
- Any number of prior hormone therapies will be allowed
- At least 4 weeks should have elapsed since prior chemotherapy (6 weeks for mitomycin C and nitrosoureas and 2 weeks for hormone therapy) or radiation therapy (2 weeks for limited-field palliative radiation to the bone)
Contacts and Locations| United States, District of Columbia | |
| Lombardi Comprehensive Cancer Center at Georgetown University | Recruiting |
| Washington, District of Columbia, United States, 20057 | |
| Contact: Claudine Isaacs 202-444-3677 isaacsc@georgetown.edu | |
| Principal Investigator: Claudine Isaacs | |
| United States, Ohio | |
| Ohio State University Medical Center | Recruiting |
| Columbus, Ohio, United States, 43210 | |
| Contact: Bhuvaneswari Ramaswamy 614-293-6401 Bhuvaneswari.Ramaswamy@osumc.edu | |
| Principal Investigator: Bhuvaneswari Ramaswamy | |
| Principal Investigator: | Bhuvaneswari Ramaswamy | Ohio State University |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01251874 History of Changes |
| Other Study ID Numbers: | NCI-2011-02552, OSU 10080, CDR0000688990, U01CA076576 |
| Study First Received: | December 1, 2010 |
| Last Updated: | June 17, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms Breast Neoplasms, Male Neoplasms by Site Neoplasms Breast Diseases |
Skin Diseases Carboplatin Antineoplastic Agents Therapeutic Uses Pharmacologic Actions |
ClinicalTrials.gov processed this record on June 17, 2013